Candida-associated denture stomatitis (CADS) is a common, recurrent disease in denture wearers and can lead to other oral health problems, systemic infections, compromised quality of life, and even death. Thus far, there are no effective treatment strategies to control CADS, and the reinfection rate is high, particularly in the elderly and those who are medically or immunocompromised. This project, building on our pilot studies sponsored by NIDCR (Rechargeable Long-term Antifungal Denture Materials, R03 DE018735) will use rechargeable, "click-on/click-off" anticandidal technology to control CADS. We have demonstrated that a small amount (10%) of methylacrylic acid (MAA) could be copolymerized with urethane denture resin monomers in the curing step without negatively affecting the physical/mechanical properties of the resulting resins. The anionic MAA moieties in the denture resins acted as a "rechargeable battery" to bind and then slowly release cationic antifungal drugs such as miconazole and chlorhexidine gluconate for a long period of time (weeks to months). The drugs could be "quenched" (washed out) by treating with ethylenediaminetetraacetic acid (EDTA) and the resins recharged with the same or different antifungal drugs. In the current project, we will apply this technique to both urethane-based and acrylic-based denture materials using various classes of topical anticandidal drugs, including azoles (clotrimazole and miconazole), polyene (nystatin) and salivary antimicrobial polypeptides (synthetic histatin 5). The biocompatibility and anticandidal efficacy of the new systems will be evaluated in vitro with human oral epithelium-Candida and reconstituted human epithelium (RHE)-Candida co-culture models. The risk of developing microbial resistance will also be tested. The specific aims of the proposed research are to: (1) fabricate new acrylic and urethane rechargeable anticandidal denture materials, and characterize the physical/mechanical properties of the new materials, (2) formulate the anticandidal drug-containing denture materials, establish drug binding/releasing kinetics, and evaluate the "click-on/click-off" anticandidal technology of the new denture materials, and (3) evaluate in vitro the biocompatibility and anticandidal activity of the new denture materials and the risk of microbial resistance to the materials. The proposed rechargeable, "click-on/click-off" anticandidal denture materials can activate or terminate antifungal drug treatment based on clinical needs. The rechargeable feature will allow switching to more potent/effective drugs to enhance anticandidal potency and/or minimize the risk of fungal resistance, leading to a personalized therapeutic strategy for CADS and related diseases. PUBLIC HEALTH RELEVANCE: Candida-associated denture stomatitis (CADS) is a common, recurring disease that seriously affects patients'oral health and wellbeing. Management and prevention of CADS is a significant clinical challenge. This project will develop new denture materials that provide sustained and rechargeable anticandidal activity with the unique features of "click-on/click-off" drug delivery based on clinical infection status. The technology can provide personalized CADS treatment and prevention, and may also be needed to develop next generation antimicrobial catheters, endotracheal tubes, and related devices to fight infection and develop safer healthcare environment.